DE3141498A1 - Pharmaceutical containing kallikrein and process for its preparation - Google Patents

Abstract

The present invention relates to pharmaceuticals which contain 79 to 99.7% by weight of lactose and, where appropriate, ancillary substances customarily used in the formulation of pharmaceuticals, and to a process for the stabilisation of kallikrein in which kallikrein and lactose are dissolved in water or a water/solvent mixture, where appropriate with the addition of phosphate as buffer, and subsequently the resulting solution is freeze- or spray-dried.

Description

Medicines containing kallikrein and method too

Its manufacture The invention relates to containing medicaments Rallikrelnç stabilized kallikrein and process for their preparation.

It is known to produce highly effective enzymes by dry mixing with inert ones To bring excipients into a dilution that is manageable for pharmaceutical purposes, however, there are disadvantages, in particular the homogeneity of the products produced in this way Mixtures.

It is also known to use enzyme-containing solutions with inert auxiliaries spray in cold gases, expose the frozen droplets to a vacuum and in this way to dry such enzymes in admixture with the inert excipients. However, these methods cannot be used for pharmaceutical purposes because the Product comes into contact with the coolant and purity problems arise as a result can result. On the other hand, it is such an elaborate one procedure uneconomical for pharmaceutical purposes.

Finally, DE-AS 2 140 747 describes a method for mixing of solid biological substances described with other solid substances. The biological one Substance is combined with a sugar that can be sublimated to dryness in an aqueous one Solvent dissolved. The resulting products are then freeze-dried Solution.

It has now been found that highly effective kallikrein can be obtained by working together Dissolve with lactose in water or in a water-solvent mixture, if necessary stabilize with the addition of a buffer and subsequent freeze-drying or spray-drying and can bring in high dilutions.

Accordingly, the invention relates to medicaments containing kallikrein and lactose and optionally phosphate as a buffer and optionally customary excipients used in the formulation of medicinal products.

Buffers, preferably phosphates, can be in the mixture in amounts of 0.1 to 2 wt .-% be included. Sodium mono- and / or diphosphate is preferred used in amounts of 0.05 to 0.5 mg / 100 KE.

Lactose is essential in the medicaments according to the invention higher concentration than the kallikrein. The medicaments preferably contain 79 to 99.7% by weight of lactose and 0.2 to 20% by weight of kallikrein and optionally 0.1-2% by weight of a buffer, preferably phosphate.

The proportion of lactose to kallikrein is preferably between 15 to 25 kallikrein units (WEa per gm mixture. Lactose is particularly preferred used in concentrations of 85 to 99% by weight, based on the kallikrein.

The freeze- or spray-dried product is sieved and can be due to easy to various pharmaceutical products due to the high degree of dilution, Particularly preferred to make tablets, to be further processed by the special Use of lactose will keep the enzymatic activity of the kallikrein for a long time Period stabilized. The drop in content of the product is better by a factor of 10 compared to pure kallikrein when stored under comparable conditions (see Fig.).

Another object of the invention is a method for stabilization of kallikrein, which consists of kallikrein and lactose in water or in one Water-solvent mixture, optionally with the addition of phosphate as a buffer to dissolve and then the solution obtained, optionally after sterile filtration Freeze- or spray-dry.

Furthermore, the use of kallikrein with 99E7 to 79% by weight lactose as well as customary auxiliaries in the manufacture of pharmaceuticals, if applicable and the use of lactose to stabilize kallikrein is still an issue the invention In the figure is the decrease in enzymatic activity at a storage temperature of 650C, based on the initial content in%, (ordinate) plotted against time in days (abscissa). It means: Curve 1: Kallikrein (+ buffer if necessary) + lactose (13.3 KE / mg) curve 2: pure alkali + lactose (10.5 KE / mg) Curve 3: kallikrein ((121.1 KE / mg) curve 4: pure kallikrein (743 KE / mg) The inventive The method has the advantage that it consists of particularly homogeneous, solid mixtures Kallikrein and sugar are to be made. Another advantage is that with the inventive method kallikreine of different enzymatic activities can be adjusted to a constant content, what the further processing to pharmaceutical dosage forms much easier.

The kallikrein-containing mixtures can be used in a corresponding manner necessary dosage and the exact content required proportion to one pharmaceutical granules mixed and then this mixture into tablets The kallikrein-containing mixture can also be pressed in sterilized water dissolved and freeze-dried in a required amount in sterilized ampoules will. After drying, the ampoules are melted shut.

Example 1 Kallikrein active ingredient is used with an enzymatic Activity from 50 - 140.0 SE / mg. An amount corresponding to the desired dilution is dissolved in water (e.g. 17 million KE in 1 l of water).

This solution is with a cooled aqueous solution of about 0.8 kg of lactose and 8.5 g of Na2HPO4 mixed in 3 l of water. The combined solutions become sterile filtered through a membrane filter, then frozen and placed under the usual conditions in a freeze dryer over a period of about a2 hours dried, the temperature of the product not exceeding -140C. The final drying takes place at room temperature.

The product temperature is monitored with a thermistor and accordingly regulated. After drying is complete, the product is passed through a 0.8 sieved and packed in airtight and moisture-tight containers.

Example 2 The above-described kallikrein - lactose - buffer solution 1 g of disodium ethylenediamide tetraacetate is added.

The solution is sprayed into a spray tower with a supply air temperature of 1200C. The product temperature is a maximum of 600C. The template behind the air separator is changed continuously and the product cools down quickly.

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Claims (8)

Claims 1. Medicaments containing kallikrein and 99.7 to 79% by weight lactose and, if appropriate, customary in the formulation of pharmaceuticals auxiliary materials used. 2. Medicament according to claim 1, containing phosphate as a buffer. 3. Medicament according to claim 1 or 2, containing mono- and / or Diphosphates in amounts of 0.05 to 0.5 mg / 100 kallikrein units. 4. A method for stabilizing kallikrein, characterized by that one kallikrein and lactose in water or in a water-solvent mixture optionally with the addition of phosphate as a buffer and then dissolves the resulting solution freeze-dried or spray-dried 5. The method according to claim 4, characterized characterized in that the solution is filtered sterile before drying. 6. Kallikrein stabilized by adding lactose. 7. Use of kallikrein and 99.7 to 99% by weight lactose as well customary auxiliaries, if applicable in the manufacture of pharmaceuticals. 8. Use of lactose to stabilize kallikrein.